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WO1996028145A9 - Emploi de donneurs d'oxyde d'azote ou d'inhibiteurs d'oxyde d'azote afin de modifier la dilatation et l'extensibilite du col uterin - Google Patents

Emploi de donneurs d'oxyde d'azote ou d'inhibiteurs d'oxyde d'azote afin de modifier la dilatation et l'extensibilite du col uterin

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Publication number
WO1996028145A9
WO1996028145A9 PCT/US1996/003540 US9603540W WO9628145A9 WO 1996028145 A9 WO1996028145 A9 WO 1996028145A9 US 9603540 W US9603540 W US 9603540W WO 9628145 A9 WO9628145 A9 WO 9628145A9
Authority
WO
WIPO (PCT)
Prior art keywords
nitric oxide
cervical
induction
llβ
estra
Prior art date
Application number
PCT/US1996/003540
Other languages
English (en)
Other versions
WO1996028145A1 (fr
Filing date
Publication date
Priority to PL96322252A priority Critical patent/PL183461B1/pl
Priority to SK1241-97A priority patent/SK124197A3/sk
Priority to AU53117/96A priority patent/AU713172B2/en
Priority to NZ305169A priority patent/NZ305169A/en
Priority to DE69637313T priority patent/DE69637313T2/de
Priority to UA97105013A priority patent/UA57703C2/uk
Priority to KR10-2003-7009932A priority patent/KR100434239B1/ko
Application filed filed Critical
Priority to EP96909707A priority patent/EP0814785B1/fr
Priority to JP52783596A priority patent/JP4579349B2/ja
Publication of WO1996028145A1 publication Critical patent/WO1996028145A1/fr
Publication of WO1996028145A9 publication Critical patent/WO1996028145A9/fr
Priority to IS4555A priority patent/IS4555A/is
Priority to NO19974204A priority patent/NO318598B1/no

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Definitions

  • the present invention relates to the regulation of cervical dilatation and extensibility by the use of nitric oxide donors and/or substrates or nitric oxide inhibitors.
  • Parturition expulsion of the fetus from the uterus
  • a softening of the connective tissue of the cervix so that it will stretch and dilate sufficiently to allow the fetus to be expelled. This softening is known as "ripening”.
  • prostaglandin E2 This is used as a vaginal gel or tablet or as a gel placed in the cervix.
  • One worry about the use of prostaglandin E2 is that there is a possibility of hyperstimulation of the uterus, leading to excessively strong myometrial contractions before the cervix is ripened and therefore before a comfortable or safe birth is possible.
  • the ideal preparation would soften and efface the cervix without causing myometrial contractions. This would allow the subsequent contractions (induceable if necessary with a small dose of prostaglandin) to deliver the baby with a minimum of resistance.
  • the antiprogestins such as RU486 would meet these requirements, but the problem with this drug is that it has associated antiglucocorticoid activity which might be detrimental to the fetus.
  • Nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991; Ignarro, 1991).
  • Nitric oxide is an important mediator of relaxation of the muscular smooth muscle (Montada, Palmer and Higgs, 1991) and was formerly known as EDRF (endothelin-derived relaxing factor) (Furchgott und Zawadzki, 1980; Moncada, Palmer and Higgs, 1991).
  • Nitric oxide is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least different isoforms of a flavin-containing enzyme, nitric oxide synthase (Montada, Palmer and Higgs, 1991). Nitric oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglyceri ⁇ , glyceryl trinitrate, SIN-1, isosorbid mononitrate, isosorbid dinitrate, etc.
  • nitric oxide has been shown to be competitively inhibited by analogues of L- arginine; NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-argi ⁇ ine (MMA), N-iminoethyl-L-amithine (L-NIO), L-monomethyl-Larginine (L-NNMA), L-NG- methylarginine (LNMA), Nw-nitro-L-arginine (L-NA) and A inoguanidine.
  • L-NAME NG-nitro-L-arginine methyl ester
  • MMA NG-monoethyl-L-argi ⁇ ine
  • L-NIO N-iminoethyl-L-amithine
  • L-NNMA L-monomethyl-Larginine
  • LNMA L-NG- methylarginine
  • L-NA Nw-nitro-L-arginine
  • nitric oxide synthase-stimulated uterine contractility indicates that the tonic release of nitric oxide maintains the uterus in a quiescent state.
  • treatment of pregnant guinea pigs with L-NAME induced preterm labor.
  • treatment of rat uterine strips in vitro with L-arginine inhibited contractions.
  • nitric oxide may be important in uterine quisence during pregnancy, and exogenous nitric oxide may be useful in controlling preterm labour.
  • Nitric oxide synthase (NOS) activity was demonstrated in multiple structures within the gravid rat uterus by Natuzzi et al. (Biochem. and Biophys. Res. Commun., 194, No.l, 1-8,(1993)) and they conclude NOS to be present within multiple structures of the gravid rat uterus. Reduction in NOS activity at parturition suggests NO may contribute to the maintenance of uterine contractile quisence during gestation.
  • a nitric oxide inhibitor such as L-NAME inhibits cervical ripening but stimulates uterine contractions in pregnant guinea pigs
  • the NO-system plays an important role in the control of uterine cervix, the NO production being increased during the ripening process of the cervix.
  • nitric oxide donors and/or substrates can be used to induce cervical ripening
  • a local application of a nitric oxide-inhibitor can be used to prevent or inhibit cervical ripening, e.g. for the treatment of cervical insufficiency (too early cervical ripening) or preterm labour.
  • the present invention is directed to the use of nitric oxide donors and/or substrates or nitric oxide inhibitors for manufacture of a medicament for regulating cervical dilatation and/or extensibility.
  • the present invention involves the use of either
  • At least one nitric oxide inhibitor for manufacture of a medicament to be administered locally e. g. intracervically or intravaginally
  • a nitric oxide inhibitor for manufacture of a medicament to be administered locally e. g. intracervically or intravaginally
  • locally e. g. intracervically or intravaginally
  • cervical rirening for treatment of cervical insufficiency or preterm labor.
  • nitric oxide donor and/or substrate or nitric oxide inhibitor are all the compounds known to the persons skilled in the art as having the required properties; the compounds mentioned under "Description of related art" are preferred.
  • the nitric oxide donor and/or substrate (a) can further be used in combination with (i) at least one of an antiprogestin, a prostaglandin and/or a cytokine.
  • antiprogestins are onapristone (ll ⁇ -[4-(Dimethylamino)phenyl]-17 ⁇ -hydroxy-17 ⁇ -(3-hydroxypropyl)-13 ⁇ -estra- 4,9-diene-3-one), RU 486 (ll ⁇ -[4-(Dimethylamino)phenyl]-17 ⁇ -hydroxy-17 ⁇ -(l- propinyl)estra-4,9-diene-3-one), (Z)-ll ⁇ -[4-(Dimethylamino)phenyl]-17 ⁇ -hydroxy-17 ⁇ -(3- hydroxy-l-propenyl)estr-4-ene-3-one (EP-A 0 404 283), ll ⁇ -(4-Acetylphenyl)-17 ⁇ -hydroxy- 17 ⁇ -(l-propinyl)estra-4,9-diene-3-one (EP-A 0 190 759),4',5 , -Dihydro-ll ⁇ -[4- (dimethylamino)phen
  • prostaglandins sulprostone (PGE2) or gemeprost can be used for instance.
  • interleukin-8 or interleukin-l ⁇ The most prominent representatives for the cytokines are the interleukin-8 or interleukin-l ⁇ . These listings are not to be regarded as exhaustive.
  • the nitric oxide inhibitor (b) can further be used in combination with (ii) at least one of a progestin and/or a cyclooxygenase inhibitor (e. g. COX-1- and COX-2-inhibitors).
  • a progestin and/or a cyclooxygenase inhibitor e. g. COX-1- and COX-2-inhibitors.
  • progestin the naturally occuring progesterone is preferred but it is also possible to use one or more of the numerous synthetic progestins known to the artisan for use in oral contraceptives, for example levonorgestrel, cyproterone acetate, gestoden, drospirenone, desogestrel, 3-ketodesogestrel, dienogest etc..
  • the cyclooxygenase inhibitor can be for example aspirin (COX-1- and COX-2-inhibitor). Further examples of COX-2 inhibitors can be taken from: Robert Aslanian, Nicholas I. Carruthers, James J. Kaminski; Cyclooxygenase 2: A Novel Target for Therapeutic Intervention, Exp. Opin. Invest. Drugs, 1994, 3 (12), 1323-1325, for instance the compounds Sc-58125 (GD Searle), DuP-697, flusolide [6-(2,4-difuorophenoxy)-5-methylsulfonylamino-l- indanone], Sc-57666 (GD Searle), L-745 337 (Merck Frosst), NS-398 (Monsanto).
  • the invention provides the use of these compounds of the invention in connection with birth or abortion. In this situation of pregnancy the cervix is pre-treated. The hormones during pregnancy alter the cervix which is then inclined to respond effectively to other stimulants.
  • the invention provides the use of the compounds under (a) of the invention in connection with surgical procedure and diagnostic procedure. Therefore, the compounds under (a) of the invention can, optionally in combination with the compounds mentioned under (i), be used for manufacture of medicaments for the following indications:
  • the invention provides the use of these compounds of the invention in indications which require the prevention of too early cervical ripening or where the cervix has to be kept rigid. Therefore the compounds under (b) of this invention can, optionally in combination with the compounds mentioned under (ii), be used for manufacture of medicaments for the following indications:
  • the compound can be used for human and non-human females. Human beings are the preferred group for this treatment.
  • the nitric oxide donor and/or substrate (a) or the s. ⁇ ric oxide inhibitor (b) can be administered in any way in which, directly or indirectly, it will reach the cervix.
  • it is conveniently applied intravaginally or directly to the cervix, e.g. typically as a gel or cream. It can also be injected into the cervical tissue or by a blunt needle into the cervical channel. It can also be applied extra-amniotically, i.e. between the uterine wall and the amniotic sac, using a catheter.
  • the preferred formulation is a gel or cream, but it can be applied as softenable capsules, liposomes or in a slow release formulation, or as an aqueous solution, e.g. a saline or protein- containing solution.
  • the formulation can be achieved by methods known to the persons of ordinary skill in the art.
  • the a ⁇ tiprogestin can be formulated for systemic or topical administration.
  • the prostaglandin as well as the cytokine will be preferably formulated for local use.
  • the compounds under (ii) can be formulated for local or systemic application.
  • the compounds as under (a) of the invention exhibit pharmacological activity in induction of cervical ripening and may, therefore, be useful as a pharmaceutical agents.
  • the compounds as under (b) of the invention exhibit pharmacological activity in preventing cervical ripening and may, therefore, be useful as a pharmaceutical agents.
  • Example 1 The measurement of the cervix ripening is described in Example 1.
  • Sodium nitroprusside and other nitric oxide donors show an effect on the cervical ripening at concentrations of from about 0.03 mM - 100 M (1.8 ⁇ g - 6 mg/application) when locally administered to pregnant female guinea-pigs.
  • the appropriate dosage will, of course, vary depending upon, for example, the compounds of the invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a concentration from about 0.03 - 100 mM in the local formulation, preferred at a concentration of about 10 mM.
  • the compounds of the invention can be administered 6 to 48 hours before the final ripening of the cervix.
  • the ripening can be proceeded by induction of labour with an oxytocic compound.
  • the compounds can be administered in one or more dosages administered in a series with a distance of some hours or one day.
  • the compounds of the invention may be administered by any conventional route, in particular in form of gel, ointment or local injection (at a concentration of about 0.03 to 100 mM).
  • Sodium nitroprusside and other nitric oxide donors show an effect on the cervical ripening at concentrations of from about 0.03 mM - 100 mM (1.8 ⁇ g - 6 mmg/application) when administered to female guinea-pigs which are not pregnant.
  • the appropriate dosage will, of course, vary depending upon, for example, the compounds of the invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a dosage from about 0.03 mM - 100 mM (1.8 ⁇ g - 6 mmg/application), preferred at a concentration of about 10 M.
  • These compounds of the invention can be administered 24 or 48 hours before the final ripening of the cervix.
  • the compounds can be administered in one or more dosages administered in a series with a distance of some hours or one day.
  • the compound of the invention may be administered by any conventional route, in particular in form of gel, ointment or local injection.
  • Examples of human dosage ranges of typical NO-substrates and NO-donors are:
  • NO-donors or NO-substrates are used in bioequivalent amounts.
  • Examples of dosage ranges of typical NO-inhibitors are:
  • L-NMA 1 to 50 mg/kg/day.
  • Aminoguanidine 0.1 to 100 mg/kg/day.
  • Other NO-inhibitors are used in bioequivalent amounts.
  • Dosage range for RU 486 25-600 mg/day per os.
  • prostaglandins such as PGE2 are used in bioequivalent amounts.
  • the prostaglandins can also be used locally intracervically in gel, intravaginally in gel or as tablets.
  • Dosage range for COX-2 inhibitors 0.1 - 100 mg/kg/day.
  • Dosage range for IL-8 100 ng - 500 g/day; dosage range for IL-l ⁇ : 100 ng - 500 ⁇ g/day.
  • Bioequivalent amounts of other compounds than those mentioned above can be determined by the methods as disclosed in the examples as such amounts which lead to comparable effects in the cervix as the specifically disclosed amounts under otherwise analogous conditions.
  • Figure 1 shows the effect of sodium nitroprusside on cervical ripening in pregnant guinea pigs. Animals are treated as described in Example 1.
  • the upper panel shows the initial dilatation (in mm) during extensibility measurement; the lower panel demonstrates the effect on the extensibility (slope of the regression curve).
  • the data are presented as box plots.
  • the vertical lines represent the range from the lowest to the highest amount.
  • the height of the box, the horizontal line, and asterisk describe the inter quartile range, median, and mean value, respectively.
  • Figure 2 shows the effects of L-NAME on the uterine cervix in pregnant guinea pigs.
  • the upper panel shows the initial dilatation (in mm) during extensibility measurement; the lower panel demonstrates the effect on the extensibility (slope of the regression curve [N/mm]).
  • Data are presented as box-plots as described for Figure 1.
  • Figures 3 to 5 show extensibility of the cervix of rats after treatment with L-NAME (50 mg/rat) or without treatment.
  • Figure 6 shows increase in duration of delivery and pup interval (time between birth of pups during L-NAME treatment.
  • Figures 7 to 9 show NO production during normal cervical dilatation (ft), after progesterone ( ), antiprogesti ⁇ e (ft), and LPS (ft).
  • the isolated cervix is mounted between two hooks inserted through each canal of the cervix.
  • the cervix is extended by moving the hook for 0.1 mm, then the hook is fixed and the cervix allowed to relax for 2 minutes. This is repeated until either the cervix ruptures or at least the yield point has been reached, i.e. the envelope of the load vs. time curve becomes non-linear (see the publication CONRAD, J.T. and UELAND, K. (1979) Am J Obstet Gynecol 133: 11 - 13)
  • the force vs. stretch ratio curve is studied. This curve is obtained by taking the maximum force at each extension stage and the associated stretch ratio, which is defined as displacement divided by the initial dilation. The slope of a regression line through the linear portion of this curve is taken to quantify the effect of treatment on cervical extensibility. A decrease in the slope represents an increase in the cervical extensibility (ripening effect).
  • the measurement of cervical extensibility (parameters: slope of the regression line, initial dilatation) was performed on d44 p.c.
  • the gel is administered by the following method: After introduction of the speculum into vagina, 200 l of cellulose gel with or without SNP is injected through ca. 100 mm long blunt needle into cervical channel.
  • the gel comprises the compounds of the invention in PBS (phosphate buffered saline, see L. HUDSON and F.C. HAY.(1980) Practical Immunology, Oxford, sec. edition) with 3 % (w/v) hydroxylethylcellulose.
  • PBS phosphate buffered saline
  • the control group receives a gel comprising 3 % (w/v) hydroxylethylcellulose in PBS.
  • the mechanical properties of the cervix are measured by the method described above which allows the quantification of cervical extensibility and dilation of the uterine cervix under isometric conditions.
  • Example 1 The results of the Example 1 are shown in Figure 1.
  • the upper panel shows the slopes of the regression line which is the parameter of the extensibility of the cervix.
  • the lower panel demonstrates the initial dilatation in mm of the cervix.
  • SNP (0.1 M) was administered intracervically in 0.2 ml PBS buffer containing 3% hydroxycellulose twice on days (d) 42-43 post coitum (p.c), and the effects were assessed on day 44 p.c. by morphological evaluation.
  • the control animals were treated with the vehicle. All cervices used for the morphological evaluation were obtained after in situ fixation by vascular perfusion. The perfusion procedure was performed on day 50 p.c. between 9-10 a.m. under anesthesia with 1,5 ml pentobarbital i.m. (60 mg/ml).
  • a cannula was implanted into the abdominal aorta beneath the branching of renal arteries; animals were perfused with cacodylate buffer, pH 7,4 for 60 - 90 sec, followed by fixation with 2,5% glutaraldehyde in cacodylate buffer, pH 7.4, for 6 - 10 min at a pressure of 80-100 cm. H2O. Cervices were excised and dissected free of adjacent tissues, then fixed at 4°C in the same fixative. After buffer wash, the material was post-fixed for 2h in cold cacodylate buffered 1% OsO4, dehydrated in graded series of ethanol and embedded in Araldite epoxy resin.
  • Transverse semithin survey sections 1 - 2 m in thickness, were cut from each of these specimens and were stained with 1% toluidine blue in sodium borate to be examined by light microscopy. This enabled to study the entire cervix, thereby providing an overview of the distribution of the various cell populations in the cervix. Thereafter, small specimens (1 - 2 mm ⁇ ) were trimmed off the transverse cervix block and ultrathin sections were prepared with glass or diamond knives on a Reichert OmU3 microtome and mounted on single slot Formvar-coated copper grids. They were stained with uranyl acetate and lead citrate and examined with a Zeiss EM - 10 electron microscope at 60-80 kW.
  • Pregnant guinea pigs were treated with L-NAME (12.5 mg/day/animal s.c.) on days 48 and 49 p.c.
  • the cervical extensibility and dilatation were measured on day 50 p.c, i.e. two days after the start of tratment. The measurement was conducted as described in Example 1.
  • the results of Example 3 are shown in Fig. 2. Both the initial dilatation and cervical extensibility (increase in slope) were decreased in comparison with the control group.
  • the control group was treated with the vehicle:
  • Figure 6 which is based on a similar experiment as that described in Example 4 shows that during L-NAME treatment (50 mg/day) of pregnant rats the duration of delivery and the pup intervall, that is the time between the birth of the single pups, is markedly increased. This clearly shows that nitric oxide inhibitors prevent cervical ripening in rats.
  • the nitric oxide generating activity measured in vitro as a total nitrite accumulation in the cervical and uterine tissues was estimated using a method described in: Yallampalli C, Garfield RE, Byam-Smith M (1993): Nitric oxide inhibits uterine contractility during pregnancy but not during delivery, Endocrinology 133: 1899-1902. Briefly, small pieces of cervical or uterine tissues obtained from delivering rats (day 22-23 of pregnancy), o ⁇ apristone-treated (10 mg on day 18 p.c, s.c.) and from vehicle-treated rats on days 18-21 p.c. (controls) were incubated in minimum essential medium (MEM) with L-arginine with or without L-NAME for 24 h at 37°C. The medium was assayed for total nitrites using the Griess reagent.
  • MEM minimum essential medium
  • Nitrite production in the uterine (myometrial) tissue the production dramatically decreases in the uterine samples obtained from delivering animals in comparison with day 18 of pregnancy (Yallampalli et al., loc. cit).
  • Nitrite production in the cervical tissue Fig. 7: there is a significant increase in NO production in the cervix obtained from delivering animals in comparison with pregnant rats on days 18-22 p.c.

Abstract

Cette invention concerne un procédé permettant de modifier la dilatation et l'extensibilité cervicales grâce à l'emploi de donneurs et/ou de substrats d'oxyde d'azote ou d'inhibiteurs d'oxyde azote. On peut utiliser à cette fin (a) soit au moins un donneur et/ou substrat d'oxyde d'azote afin de fabriquer un médicament qui sera administré localement par voie intracervicale ou intravaginale afin de déclencher le mûrissement cervical, (b) soit au moins un inhibiteur d'oxyde d'azote afin de fabriquer un médicament qui sera administré localement par voie intracervicale ou intravaginale afin de traiter une insuffisance cervicale ou un travail préterme.
PCT/US1996/003540 1995-03-14 1996-03-14 Emploi de donneurs d'oxyde d'azote ou d'inhibiteurs d'oxyde d'azote afin de modifier la dilatation et l'extensibilite du col uterin WO1996028145A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP96909707A EP0814785B1 (fr) 1995-03-14 1996-03-14 Emploi de donneurs d'oxyde d'azote ou d'inhibiteurs d'oxyde d'azote afin de modifier la dilatation et l'extensibilite du col uterin
AU53117/96A AU713172B2 (en) 1995-03-14 1996-03-14 Use of nitric oxide donors or nitric oxide inhibitors for regulating cervical dilatation and extensibility
NZ305169A NZ305169A (en) 1995-03-14 1996-03-14 Nitric oxide donors or inhibitors used to regulate cervical dilation and extensibility
DE69637313T DE69637313T2 (de) 1995-03-14 1996-03-14 Verwendung von stickstoffoxyddonoren oder -antagonisten zur regulierung der dehnung der zervix
UA97105013A UA57703C2 (uk) 1995-03-14 1996-03-14 Спосіб стимуляції та спосіб інгібування дозрівання шийки матки
PL96322252A PL183461B1 (pl) 1995-03-14 1996-03-14 Zastosowanie donorów i/lub substratów tlenku azotu lub inhibitorów tlenku azotu dla wytwarzania środka leczniczego dla regulacji rozszerzania lub rozciągliwości szyjki macicy
SK1241-97A SK124197A3 (en) 1995-03-14 1996-03-14 Use of nitric oxide donors or nitric oxide inhibitors for regulating cervical dilatation and extensibility
KR10-2003-7009932A KR100434239B1 (ko) 1995-03-14 1996-03-14 경관 팽창 및 신장 조절을 위한 산화질소 공여체 또는산화질소 억제제의 용도
JP52783596A JP4579349B2 (ja) 1995-03-14 1996-03-14 子宮頸の拡大及び拡張度を制御するための酸化窒素供与体及び／又は基質又は酸化窒素インヒビター
IS4555A IS4555A (is) 1995-03-14 1997-09-05 Notkun köfnunarefnisoxíð gjafa eða köfnunarefnisoxíð lata til að tempra leghálsvíkkun og þenslu
NO19974204A NO318598B1 (no) 1995-03-14 1997-09-12 Anvendelse av nitrogenoksiddonorer eller nitrogenoksidinhibitorer for regulering av cervixdilatasjon og -utvidelsesevne

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95250059 1995-03-14
EP95250059.3 1995-03-14

Related Child Applications (1)

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US09/236,085 Continuation US6333350B1 (en) 1995-03-14 1999-01-25 Use of nitric oxide donors and/or substrates or nitric oxide inhibitors for regulating cervical dilatation and extensibility

Publications (2)

Publication Number Publication Date
WO1996028145A1 WO1996028145A1 (fr) 1996-09-19
WO1996028145A9 true WO1996028145A9 (fr) 1996-12-05

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US (1) US6333350B1 (fr)
EP (1) EP0814785B1 (fr)
JP (1) JP4579349B2 (fr)
KR (2) KR100434238B1 (fr)
CN (1) CN1151781C (fr)
AT (1) ATE377417T1 (fr)
AU (1) AU713172B2 (fr)
CA (1) CA2214779A1 (fr)
CZ (1) CZ292395B6 (fr)
DE (1) DE69637313T2 (fr)
ES (1) ES2297838T3 (fr)
HU (1) HUP9800826A3 (fr)
ID (1) ID20742A (fr)
IL (1) IL117496A (fr)
IS (1) IS4555A (fr)
MX (1) MX9707007A (fr)
MY (1) MY116500A (fr)
NO (1) NO318598B1 (fr)
NZ (1) NZ305169A (fr)
PL (1) PL183461B1 (fr)
RU (1) RU2199346C2 (fr)
SK (1) SK124197A3 (fr)
TW (1) TW421594B (fr)
UA (1) UA57703C2 (fr)
WO (1) WO1996028145A1 (fr)
ZA (1) ZA962089B (fr)

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EP0889724A1 (fr) * 1996-02-27 1999-01-13 Rpms Technology Limited Inhibiteurs selectifs de cox-2 destines a la maitrise de la periode de travail et des contractions uterines
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
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RU2267133C2 (ru) * 2004-03-04 2005-12-27 Государственное учреждение "Ивановский научно-исследовательский институт материнства и детства им. В.Н. Городкова" Минздрава России Способ диагностики угрозы преждевременных родов
WO2006089561A1 (fr) * 2005-02-23 2006-08-31 Abbas Abdelsalam Ghazi Compositions pharmaceutiques contenant des acides organiques utiles pour le ramollissement et la maturation du col de l’uterus.
US8828981B2 (en) 2007-02-06 2014-09-09 George Creasy Progesterone for the treatment or prevention of spontaneous preterm birth
CN102283827A (zh) * 2008-10-16 2011-12-21 四川维信医药科技有限责任公司 单硝酸异山梨酯的新用途

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US5508045A (en) 1992-10-09 1996-04-16 The Regents Of The University Of California Method and agents for control and management of labor during pregnancy
US5895783A (en) * 1993-07-16 1999-04-20 Schering Aktiengesellschaft Treatment of preeclampsia and preterm labor with combination of progestational agent and a nitric oxide synthase substrate and/or donor
JP4015185B2 (ja) * 1993-11-16 2007-11-28 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 酸化窒素シンターゼ基質及び／もしくは供与体、又は酸化窒素阻害剤による子宮収縮障害の処置
US5550369A (en) 1994-02-28 1996-08-27 Electro-Pro, Inc. Triangulation position detection method and apparatus
KR100434238B1 (ko) 1995-03-14 2004-07-16 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 경관팽창및신장조절을위한산화질소공여체또는산화질소억제제의용도

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